BP1 and Nuclear Hormone Signaling in Breast Cancer

描述(申请人提供)：这是一项名为《造血系统疾病的治疗策略》的以患者为中心的研究的职业中期研究人员奖：PA-00-005。血细胞的形成代表了干细胞、构成基质微环境的细胞和生长调节蛋白之间的复杂相互作用，它们以可溶的和局部的形式存在。这些相互作用产生了大量和多样化的细胞，这些细胞在身体广泛分离的部分发挥作用，运输氧气，防御感染性病原体，并为凝血提供刺激。损害血细胞发育过程的异常，如骨髓发育不良和急性髓系白血病(AML)；以及癌症，可导致危及生命的疾病以及谱系特异性骨髓抑制或全血细胞减少，从而导致显著的发病率和死亡率。这项建议侧重于开发、实施和指导以科学为基础、以假设为驱动的试验性临床调查，旨在利用这些特定疾病的内在生物学特征。候选人目前(目前得到资助)和新的(得到K24支持)临床研究工作有三个截然不同的中心假设：1)干扰或逆转转录抑制的药物的治疗应用将分别在AML和MDS中发挥临床作用；2)抑制自分泌和微环境呈现的生长因子，它们有助于推迟程序性细胞死亡，如慢性淋巴细胞白血病(CLL)，这是一种潜在有效的新治疗方法；3)细胞因子对红细胞生成的抑制导致癌症贫血；克服细胞因子抑制的策略应增加癌症患者的红细胞生成，进一步减少这一人群的临床贫血问题。这项申请的一个重要部分涉及到关键初级教员和血液学/肿瘤学研究员的积极指导，他们选择将学术临床研究作为职业道路。这一指导计划包括：1)与NIH资助的临床研究培训计划(K30)(候选人担任首席研究员)和IRB临床研究行为课程一起参加特定课程；2)直接监督，包括每周会议：(A)方案和IND开发；(B)应计、数据和监管审查；(C)手稿和演示文稿准备。

DESCRIPTION (provided by applicant): This is a "Midcareer Investigator Award in Patient-Oriented Research: PA-00-005" entitled Therapeutic Strategies in Disorders of Hematopoiesis. The formation of blood cells represents a complex interaction between stem cells, ceils making up the stromal microenvironment and growth regulatory proteins, which are presented in soluble and localized forms. These interactions give rise to an enormous number and diversity of cells that function in widely separated parts of the body to transport oxygen, defend against infectious agents and provide stimulus for clotting. Abnormalities that impair the process of blood cell development, such as Myelodysplasia and Acute Myelogenous Leukemia (AML); as well as Cancer, can lead to life threatening illness as welt as lineage specific myelosuppression or pancytopenia resulting in significant morbidity and mortality. This proposal focuses on the development, conduct and mentoring of scientifically based, hypothesis-driven pilot clinical investigations, designed to exploit inherent biological features of these specific diseases. Three distinct central hypotheses underlie the Candidate's present (currently funded) and new (to be supported by K24) clinical research efforts: 1) the therapeutic application of agents that interfere or reverse transcriptional repression will be of clinical utility in AML and MDS respectively; 2) inhibition of autocrine and microenvironmentally presented growth factors, which contribute to delays in programmed cell death, characteristic of disorders such as chronic lymphocytic leukemia (CLL), represents a novel therapeutic approach of potential utility; and 3) cytokines inhibitory for erythropoiesis contribute to anemia of cancer; strategies to overcome cytokine inhibition should augment red blood cell production in cancer patients and further reduce the clinical problem of anemia in this population. An important part of this application concerns the active mentorship of key junior faculty and hematology/oncology fellows who have chosen to pursue academic clinical research as a career path. This mentorship program consists of: 1) participation in specific curriculum in conjunction with the NIH funded Clinical Research Training Program (K30), for which the candidate serves as the Principal investigator, and IRB course on conduct in Clinical Research; 2) direct oversight, including weekly meetings for: (a) protocol and IND development; (b) accrual, data and regulatory review; (c) manuscript and presentation preparation.